The purpose of the proposed clinical trial is to assess the efficacy of omega-3 fatty acids (03FA) in preventing recurrence in patients with bipolar disorder, type 1. Omega-3 fatty acids from fish oil (a mixture of docosahexanoic (DHA) and eicosapentanoic (EPA) acids), are polyunsaturated lipids which inhibit intracellular signal transduction in a manner comparable to lithium and divalproex, 2 drugs with efficacy in bipolar disorder. An initial 4 month, double-blind, placebo-controlled, add-on study of 03FA treatment in 30 recently ill bipolar patients revealed that the omega-3 treated group had a significantly greater duration of remission compared to the placebo group (p = 0.002 Mantel-Cox). 03FA are non-toxic, essential dietary lipids, and there were few side-effects to the 03FA treatment. This initial indication of efficacy, combined with the need for safe and effective prophylactic treatments for bipolar disorder, warrant undertaking a larger and more rigorously designed 1-year prophylactic study, to be completed over a 3-4 year funding period. In the proposed 2-site primary study, 120 outpatients with bipolar disorder, type I, will be randomly assigned to receive add-on treatment with 03FA or placebo, for one year. The primary goal of this study is to assess the prophylactic effects of 03FA in a cohort of bipolar patients with a relatively high risk of recurrence. In contrast to the pilot study, the proposed trial will tightly control the baseline clinical state and concurrent pharmacotherapy of the subjects to provide a more homogeneous bipolar population. This will be accomplished through a lead-in and stabilization phase where patients will be gradually shifted to receive a standardized regimen (lithium or divalproex). Only subjects who are euthymic or subsyndromal at the end of the lead-in period will be eligible for the 1-year prophylactic study. The following biological markers will be examined as measures of compliance with the study protocol and/or as possible predictors of response to 03FA: 1. Plasma and erythrocyte fatty acid content. 2. The niacin skin patch test (a possible marker of in vivo omega-3 fatty acid activity). 3. Preliminary development of methods to noninvasively measure the 03FA content in brain using C13 magnetic resonance spectroscopy. If 03FA are indeed effective mood stabilizers for bipolar disorder, this project would provide additional evidence of aberrant signal transduction mechanisms in the pathophysiology of bipolar disorder, and may herald the advent of a new class of rationally designed mood stabilizing drugs.